Use of Phenylbutyrate Therapy for Patients With Pyruvate Dehydrogenase Complex Deficiency. (TIGEM2-PDH)

• ClinicalTrials.gov Identifier: NCT03734263
• Recruitment Status: Completed
• First Posted: November 7, 2018
• Last Update Posted: October 13, 2021
• Sponsor: Fondazione Telethon
• Information provided by (Responsible Party): Nicola Brunetti-Pierri, Fondazione Telethon

Tracking Information

• First Submitted Date: October 25, 2018
• First Posted Date: November 7, 2018
• Last Update Posted Date: October 13, 2021
• Actual Study Start Date: October 1, 2018
• Actual Primary Completion Date: July 30, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 6, 2018)

• Efficacy: blood lactate (mmol/L) [ Time Frame: two weeks after starting therapy ]
  blood lactate (mmol/L)
• Efficacy: blood lactate (mmol/L) [ Time Frame: four weeks after starting therapy ]
  blood lactate (mmol/L)

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 6, 2018)

• Efficacy: blood pyruvate (mmol/L) [ Time Frame: two weeks after starting therapy ]
  blood pyruvate (mmol/L)
• Efficacy:urinary lactate (mmol/mol crea) [ Time Frame: two weeks after starting therapy ]
  urinary lactate (mmol/mol crea)
• Efficacy: blood pyruvate (mmol/L) [ Time Frame: four weeks after starting therapy ]
  blood pyruvate (mmol/L)
• Efficacy: urinary lactate (mmol/mol crea) [ Time Frame: four weeks after starting therapy ]
  urinary lactate (mmol/mol crea)
• Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: two weeks after starting therapy ]
  Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
• Safety and tolerability: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: four weeks after starting therapy ]
  Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Use of Phenylbutyrate Therapy for Patients With Pyruvate Dehydrogenase Complex Deficiency.
• Official Title: Pilot Clinical Trial to Investigate the Safety and Efficacy of Phenylbutyrate Therapy for Patients With Pyruvate Dehydrogenase Complex Deficiency.
• Brief Summary: In this study phenylbutyrate is used for patients with pyruvate dehydrogenase complex deficiency. The aim of the study is to investigate the safety and efficacy of therapy.
• Detailed Description: The Investigator will evaluate the safety and efficacy of a 4-weeks treatment with sodium phenylbutyrate in patients with pyruvate dehydrogenase complex deficiency. Efficacy will be evaluated based on biochemical endpoints (blood lactate and pyruvate).
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

An open-label, uncontrolled, multicentric clinical trial will be performed on pediatric patients with PDC deficiency. Enrolled subjects will receive a four-week period of treatment with NaPB; primary and secondary endpoints will be evaluated at defined time points. Before NaPB treatment, all patients will undergo a four-week period of observation during which the same parameters will be analyzed at different time points, with the aim of evaluating basal conditions in the absence of treatment.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Pyruvate Dehydrogenase Complex Deficiency

Intervention

Drug: sodium phenylbutyrate

Enrolled subjects will receive a four-week period of treatment with sodium phenylbutyrate (oral use)

Study Arms

Experimental: open label

sodium phenylbutyrate

Intervention: Drug: sodium phenylbutyrate

Publications *

• Ferriero R, Manco G, Lamantea E, Nusco E, Ferrante MI, Sordino P, Stacpoole PW, Lee B, Zeviani M, Brunetti-Pierri N. Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis. Sci Transl Med. 2013 Mar 6;5(175):175ra31. doi: 10.1126/scitranslmed.3004986.
• Ferriero R, Brunetti-Pierri N. Phenylbutyrate increases activity of pyruvate dehydrogenase complex. Oncotarget. 2013 Jun;4(6):804-5. doi: 10.18632/oncotarget.1000. No abstract available.
• Ferriero R, Boutron A, Brivet M, Kerr D, Morava E, Rodenburg RJ, Bonafe L, Baumgartner MR, Anikster Y, Braverman NE, Brunetti-Pierri N. Phenylbutyrate increases pyruvate dehydrogenase complex activity in cells harboring a variety of defects. Ann Clin Transl Neurol. 2014 Jul;1(7):462-70. doi: 10.1002/acn3.73. Epub 2014 Jun 19.
• Ferriero R, Iannuzzi C, Manco G, Brunetti-Pierri N. Differential inhibition of PDKs by phenylbutyrate and enhancement of pyruvate dehydrogenase complex activity by combination with dichloroacetate. J Inherit Metab Dis. 2015 Sep;38(5):895-904. doi: 10.1007/s10545-014-9808-2. Epub 2015 Jan 20.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 5, 2021): 1
• Original Estimated Enrollment (submitted: November 6, 2018): 10
• Actual Study Completion Date: December 30, 2020
• Actual Primary Completion Date: July 30, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Subject must be older than 3 months old and younger than 18 years old.
2. Clinical diagnosis of PDC deficiency confirmed by DNA testing showing a missense mutation in the PDHA1 gene.
3. Lactate concentration ≥ 2.5 mmol/l or ≥ 2 mmol/l, respectively in venous or arterial blood samples.
4. Provision of signed and dated informed consent form by the parents/legal guardians of the patient
5. Negative pregnancy test for women of childbearing potential, and agree to use effective form of contraception until 6 weeks post treatment.

Exclusion Criteria:

1. Frameshift or nonsense mutations of the PDHA1 gene.
2. Defects affecting any gene encoding PDC subunits other than PDHA1
3. Secondary forms of lactic acidosis (e.g. impaired oxygenation or circulation).
4. Tracheostomy or requirement for artificial ventilation.
5. Hyperlactatemia or organic acidosis associated with other metabolic disorders (e.g. biotinidase deficiency, primary disorders of gluconeogenesis, organic acidurias, primary defects of fatty acids oxidation)
6. Evidence of hepatic insufficiency, renal insufficiency, edema with sodium retention, cardiac arrhythmia, congenital heart defects, hypertension, blood dyscrasia, symptomatic pancreatitis, or inflammatory bowel disease.
7. Any clinical condition or medications known to significantly affect renal clearance.
8. Any other condition that, in the opinion of the Investigator, may compromise the safety or compliance of the patient or would preclude the patient from successful completion of the study.
9. Known allergic reactions to components of the study agent.
10. Treatment with another investigational drug or other intervention (including DCA) or participation in a clinical study with an investigational drug within 6 months prior to enrolment.
11. Pregnancy or lactation.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 3 Months to 18 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT03734263
• Other Study ID Numbers: TIGEM2-PDH
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Nicola Brunetti-Pierri, Fondazione Telethon
• Original Responsible Party: Same as current
• Current Study Sponsor: Fondazione Telethon
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Fondazione Telethon
• Verification Date: October 2021